The development of safer and more effective radioprotectors is critical to protecting civilians from unintended radiation exposure in this currently heightened nuclear threat environment. Radioprotective agents are needed to protect people not only from acute, early arising (radiation syndrome) effects, but late arising (cancer) radiation pathologies as well. Development of a radioprotector that could both decrease acute radiation effects as well as prevent development of radiation-induced cancer would be of significant benefit to an exposed population and would be more than just an incremental improvement in radioprotection. Currently there are no safe and effective radioprotectors that have been approved by the U.S. Food and Drug Administration (FDA) for human use in a non-clinical setting, i.e., dirty bomb, nuclear accident. Several drugs are in different stages of evaluation, but so far none possesses all the requisite qualities to be an optimum radioprotector. Therefore, there is a significant gap in our knowledge and identification of effective and safe non-toxic radioprotectors. Development of new pre- and postexposure treatment products that will protect against and/or mitigate the effects of short- and long-term consequences of external radiation exposure and/or internal contamination with radionuclides is critical. With the significant improvements in clinical treatments of acute radiation injury, more attention needs to be paid to prevention of radiation-induced late effects like cancer and leukemia as well.
The several radioprotective agents that are currently approved for human use are for either clinical use or very selective and limited radiation exposure situations. The most well known of these agents is amifostine which is known for its radioprotective properties and its well-understood mechanism. Although amifostine is considered the “gold standard” of radioprotectors, it is toxic to animals and humans at radioprotective doses. Strategies to overcome the toxicity of amifostine have been minimally successful by chemically modifying the parent drug or combining with other low toxicity drugs. Several other radioprotectants with highly specific indications include potassium iodide or calcium/zinc diethylenetriaminepentaacetic acid (DTPA) but have limited usefulness as systemic radioprotectors in the event of nuclear exposure to military personnel. Immuno-modulators like the androstene steroids represent a newer approach to radioprotection. The compound 5-androstenediol (5-AED) has demonstrated significant radioprotective capability in vivo at non-toxic doses (8). Its usefulness, however, could be limited due to ineffective oral delivery and injection site inflammatory responses. Additional recent approaches have included the study of neutraceuticals, i.e., alpha tocopherol, genistein, and plant flavonoids. These approaches have shown promise but are limited by the necessity for high doses, poor oral delivery systems, and low dose reduction factors (DRF). While there are a number of cutting edge technologies like bioengineered “designer” growth factors, their feasibility for use in humans is untested and unknown. Furthermore, with the exception of amifostine, none of these approaches has shown any effectiveness against late arising radiation pathologies. Amifostine however, has not received approval for use as a radioprotector for civilian or military populations. Efforts to develop a radioprotector that can prevent long-term health effects of radiation exposure have been limited and represent a significant gap in the understanding of how to protect civilian and military personnel from health hazards of ionizing radiation.
It is well known that radiation exposure can lead to cancer development and in particular to development of leukemia. Risk estimates for radiation leukemogenesis and carcinogenesis are based on experience in humans. Quantitative data on cancer induction by radiation come from populations irradiated for medical purposes (diagnostic, radiotherapy) or inadvertently to nuclear weapons. While there is significant human and animal data regarding the induction of radiation-induced cancers, there is little data regarding the development of chemopreventive approaches to preventing these late-arising radiation sequelae. Amifostine which has is well known as a radioprotector of acute radiation effects, had shown some effectiveness at preventing radiation-late effects, i.e., cancer. In cellular and animals models it has demonstrated anti-mutagenic and anti-carcinogenic properties. While amifostine would appear to have a broad usefulness as both a radiation cytoprotective and chemopreventive agent, its use as a radioprotectant is limited by its significant toxicity. Therefore it is critical to continue the search to identify radioprotective agents that could protect against both acute and long-term radiation health effects.